Prostaglandin (PG) is a family of various eicosanoids derived from arachidonic acid (Vane, J. R. et al., Am. J. Cardiol. 75, 3A-10A (1995)). Arachidonic acid is converted into an endoperoxide intermediate, prostaglandin H2 (PGH2), by cycloxygenase. There are at least two types of isoforms of cyclooxygenase (COX-1 and COX-2). COX-1 is expressed constitutively in most tissues and cells; in some cases, the expression level is elevated during cell differentiation. In contrast, the expression of COX-2 is often up-regulated upon various types of stimulations (for example, mitogen, cytokine and endotoxin). Subsequently, the product PGH2 produced by the action of COX is converted into various types of prostaglandins (e.g., PGD2 and PGF2α and prostacyclin (PGI2)) as end products by specific synthases (Tanabe, T. et al., J. Lipid. Mediat. Cell Signal. 12, 243-255 (1995)). Prostaglandins produce a variety of effects in various aspects of regulation in homeostasis and pathogenesis. For example, PGE2 regulates blood pressure, fertilization efficiency, and cell protection; prostacyclin not only contributes to the maintenance of cardiovascular system but also shows proliferation-inhibiting activity and cell-protecting activity. It has been reported that the overexpression of COX-2 in cells of epithelial cell line from gastrointestinal tract is associated with inhibition of apoptosis (Tsujii, M. et al., Cell 83, 493-501 (1995)) and PGE2 is a major product in cells (Tsujii, M. et al., Cell 93, 705-716 (1998)). In contrast, the overexpression of COX-2 in an immortalized endothelial cell line results in retardation of cell proliferation and increases the frequency of cell death (Narko, K. et al., J. Biol. Chem. 272, 21455-21460 (1997)). Prostacyclin synthase (PGIS) is expressed endogenously in endothelial cells at high levels; prostacyclin is a major derivative of PGH2 in cells (Kara, S. et al., J. Biol. Chem. 269, 19897-19903 (1994)).
It is known that the above-mentioned prostacyclin is an unstable lipid mediator whose half life is 5 to 10 minutes (Sinzinger, H. et al., Arch. Gynecol. Obstet., 243, 187-190 (1988)), and that prostacyclin plays important roles as a strong vasodilating substance and a strong endogenous inhibitor to platelet aggregation (Moncada, S. et al., N. Engl. J. Med. 17, 1142-1147 (1979)), which are presumed to be mediated by G protein-coupled receptor which increases the cAMP level (Smith, E. M. et al., J. Biol. Chem. 271, 33698-33704 (1996)). So far, prostacyclin is poorly characterized only by the presence of cell-protecting activity to various cells (for example, vascular endothelial cell, myocardial cell, gastric cell, hepatocyte, and renal cell) in addition to the well-known activity (Vane, J. R. et al., Am. J. Cardiol. 75, 3A-10A (1995)).